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Genome-Wide Diversity and Gene Expression Profiling of Babesia Microti Isolates Identify Polymorphic Genes That Mediate Host-Pathogen Interactions J

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Genome-Wide Diversity and Gene Expression Profiling of Babesia Microti Isolates Identify Polymorphic Genes That Mediate Host-Pathogen Interactions J Genome-wide diversity and gene expression profiling of Babesia microti isolates identify polymorphic genes that mediate host-pathogen interactions J. C. Silva, E. Cornillot, C. Mccracken, S. Usmani-Brown, Ankit Dwivedi, O. O. Ifeonu, J. Crabtree, H. T. Gotia, A. Z. Virji, Christelle Reynes, et al. To cite this version: J. C. Silva, E. Cornillot, C. Mccracken, S. Usmani-Brown, Ankit Dwivedi, et al.. Genome-wide diversity and gene expression profiling of Babesia microti isolates identify polymorphic genes that mediate host-pathogen interactions. Scientific Reports, Nature Publishing Group, 2016, 6, pp.35284. 10.1038/srep35284. hal-01940958 HAL Id: hal-01940958 https://hal.archives-ouvertes.fr/hal-01940958 Submitted on 30 Nov 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. www.nature.com/scientificreports OPEN Genome-wide diversity and gene expression profiling of Babesia microti isolates identify Received: 06 July 2016 Accepted: 26 September 2016 polymorphic genes that mediate Published: 18 October 2016 host-pathogen interactions Joana C. Silva1,2, Emmanuel Cornillot3,4, Carrie McCracken1, Sahar Usmani-Brown5,6, Ankit Dwivedi3,4, Olukemi O. Ifeonu1, Jonathan Crabtree1, Hanzel T. Gotia1, Azan Z. Virji5, Christelle Reynes7, Jacques Colinge4, Vidya Kumar5, Lauren Lawres5, Joseph E. Pazzi8, Jozelyn V. Pablo8, Chris Hung8, Jana Brancato6, Priti Kumari1, Joshua Orvis1, Kyle Tretina1, Marcus Chibucos1,2, Sandy Ott1, Lisa Sadzewicz1, Naomi Sengamalay1, Amol C. Shetty1, Qi Su1, Luke Tallon1, Claire M. Fraser1, Roger Frutos9,10, Douglas M. Molina8, Peter J. Krause6 & Choukri Ben Mamoun5 Babesia microti, a tick-transmitted, intraerythrocytic protozoan parasite circulating mainly among small mammals, is the primary cause of human babesiosis. While most cases are transmitted by Ixodes ticks, the disease may also be transmitted through blood transfusion and perinatally. A comprehensive analysis of genome composition, genetic diversity, and gene expression profiling of sevenB. microti isolates revealed that genetic variation in isolates from the Northeast United States is almost exclusively associated with genes encoding the surface proteome and secretome of the parasite. Furthermore, we found that polymorphism is restricted to a small number of genes, which are highly expressed during infection. In order to identify pathogen-encoded factors involved in host-parasite interactions, we screened a proteome array comprised of 174 B. microti proteins, including several predicted members of the parasite secretome. Using this immuno-proteomic approach we identified several novel antigens that trigger strong host immune responses during the onset of infection. The genomic and immunological data presented herein provide the first insights into the determinants of B. microti interaction with its mammalian hosts and their relevance for understanding the selective pressures acting on parasite evolution. Babesia microti, the primary etiologic agent of human babesiosis, is an emerging health threat worldwide and particularly in the United States. It circulates in a tick vector – mammalian reservoir host cycle, with humans as dead-end hosts. Transmission to humans is primarily effected by ticks in the genusIxodes , but can also occur 1Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore MD 21201 USA. 2Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore MD 21201 USA. 3Institut de Biologie Computationnelle, IBC, Université de Montpellier, 860 rue St Priest, Bat 5 - CC05019, 34095 Montpellier, Cedex 5, France. 4Institut de Recherche en Cancérologie de Montpellier, IRCM - INSERM U896 & Université de Montpellier & ICM, Institut régional du Cancer Montpellier, Campus Val d’Aurelle, 34298 Montpellier, Cedex 5 France. 5Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, 15 York St., New Haven, Connecticut, CT 06520 USA. 6Yale School of Public Health and Yale School of Medicine, 60 College St., New Haven, Connecticut, CT 06520 USA. 7Institut de Genomique Fonctionnelle, IGF - CNRS UMR 5203, 141 rue de la cardonille, 34094 Montpellier, Cedex 05, France. 8Antigen Discovery Inc., Irvine, CA, 92618 USA. 9Université de Montpellier, IES, UMR 5214, 860 rue de St Priest, Bt5, 34095 Montpellier, France. 10CIRAD, UMR 17, Cirad-Ird, TA-A17/G, Campus International de Baillarguet, 34398 Montpellier, France. Correspondence and requests for materials should be addressed to J.C.S. (email: [email protected]) or C.B.M. (email: [email protected]) SCIENTIFIC REPORTS | 6:35284 | DOI: 10.1038/srep35284 1 www.nature.com/scientificreports/ through blood transfusion and, rarely, through transplacental transmission1. The first documented case of human babesiosis attributed to B. microti in the United States was reported in Nantucket Island, MA in 19692. Over the past decade, there has been a significant increase in the number of babesiosis cases among both immunocom- promised and immunocompetent patients1–4. Patients with asplenia, HIV infection, cancer, hemoglobinopathy, organ transplantation, or those on immunosuppressive drugs or who acquire the infection through blood trans- fusion, manifest particularly severe disease, sometimes requiring hospital admission and occasionally ending in death or prolonged relapsing illness1,4. Current therapies for the treatment of human babesiosis consist of combinations of atovaquone plus azith- romycin or quinine plus clindamycin1,5. Although these drugs have been extensively used in recent years, qui- nine and clindamycin combination is associated with major side effects, and drug failure has been reported with atovaquone and azithromycin. In some cases treatment can be achieved with higher drug doses, longer treatment duration and/or exchange transfusion, while in others the use of alternative drugs is needed due to microbial resistance3,5–10. Furthermore, the mechanism by which these drugs exert their anti-Babesia activity has only recently begun to be elucidated. Recent studies using a short-term in vitro culture as well as immunocompromised mice have shown that, of the four drugs used for treatment of human babesiosis, only atovaquone shows efficacy against the parasite in mouse red blood cells both in vitro and in vivo11. These results, along with the shortcomings of available diagnostic tools to distinguish between past and active infection to prevent transfusion-transmitted babesiosis, have stimulated efforts to improve therapies and diagnostics11–19. There is limited knowledge of B. microti diversity in the context of pathogenesis and host-pathogen interactions20–22. Similarly, it is uncertain how parasite variability and host adaptation may impact its virulence, its successful transmission to humans, and disease diagnosis and therapy. The paucity of information about this parasite is due in part to the lack of data on genetic variation among isolates, lack of a continuous in vitro culture system for propagation of the parasite in human or mouse red blood cells, as well as the absence of tools and resources to manipulate its genome in order to characterize gene function in microbial development and virulence. Efforts aimed at understanding B. microti population diversity and structure, and differentiate between parasite genotypes, have in the past relied on the use of PCR amplification of the 18S rDNA, β -tubulin and the chaperonin-containing t-complex polypeptide 1 (CCT7) (reviewed in ref. 23). More recently, Goethert and col- leagues used a genotyping approach based on variable number of tandem repeat loci and identified at least two major populations and shed new light on the mode of expansion of the parasite in southern New England24. The first B. microti genome sequencing and analysis were conducted on an isolate named the R1 strain, which provided initial information about genome composition, structure, metabolism, and the phylogenetic placement of the species25,26. The availability of new sequencing technologies has made it possible to perform genome-wide profiling of genetic polymorphisms in a large number of species including several protozoan parasites27–31. These analyses have significantly improved our understanding of the diversity and evolution of these pathogens, pro- vided insights into their virulence, host modulation and the genetic basis of drug resistance phenotypes, and helped to develop novel approaches for disease control and prevention, and informed public health policy32–37. Herein we report a systematic and comprehensive study of the genetic and transcriptional diversity of seven B. microti isolates. Using data from genomic and transcriptomic analyses, we have re-annotated the entire genome of the reference B. microti R1 strain, characterized the genomic diversity among isolates, and identified the full complement of genes encoding the parasite’s secretome and surface proteome. We show that polymorphism in genes that encode secreted and surface proteins accounts for most of the variations found
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